One potential therapeutic approach to treat sickle cell disease (SCD) involves the administration of aryl aldehyde-containing small molecules that form Schiff base adducts with hemoglobin (HbS) and prevent sickling. The utility of this approach is inherently limited as the kinetics of Schiff base formation between an aryl aldehyde and 1-amino group of HbS is kinetically slow under physiological conditions. Our approach utilizes benign organic catalysts to create a highly reactive therapeutic (AIC) in situ that reacts with HbS at enhanced rates. In preliminary studies, the addition of just 1 mM catalyst dramatically increased Schiff base adduct formation with Hb, as measured by the changes in oxygen affinity. We hypothesize that this strategy will be clinically useful in reducing the therapeutic doses required for efficacy, thus attenuating the likelihood of adverse effects The two Specific Aims of the proposed project are: (I) determination of the optimum levels of aldehyde and catalyst required to achieve different levels of adduct formation with free Hb in solution and in SS red blood cells, and (II) establish the effect of catalyst on the Ex vivo red blood cell sickling and morphology of SS cells by microscopy, and confirm the influence of catalyst on the degree of Schiff base adduct formation using cation exchange chromatography. Phase II efforts include in vivo evaluations of catalyst influence on efficacy in a murine sickle cell model under hypoxic conditions, pharmokinetic studies including bioavailability, and the study of any adverse effects. We plan to commercialize the AIC, formed by reaction between a benign organic catalyst and aromatic aldehyde, as a novel therapeutic for the treatment of SCD. After completion of Phase II efforts, we will partner with a multinational pharmaceutical company to develop the therapeutics through clinical trials. PUBLIC HEALTH RELEVANCE: Sickle cell disease (SCD) is a genetic disorder that inflicts over 75,000 Americans and 13 million people worldwide. This project seeks to advance the use of organic catalysts to provide for improved therapeutics that treat sickle cell disease at lower clinical doses.